Neurological Outcome in Cerebrotendinous Xanthomatosis Treated With Chenodeoxycholic Acid: Early Versus Late Diagnosis Gilad Yahalom, MD,*Þ Rakefet Tsabari, MD,Þþ Noa Molshatzki, MSc,þ Lilach Ephraty, MD,*Þ Hofit Cohen, MD,§|| and Sharon Hassin-Baer, MD*Þ|| Objective: To present the long-term neurological outcome of Jewish Israeli patients with cerebrotendinous xanthomatosis (CTX) after several years of chenodeoxycholic acid (CDCA) treatment. Methods: A cross sectional observational study of all patients with a diagnosis of CTX followed in a referral outpatient clinic during the years 2003Y2012. Results: Eighteen patients (10 men) from 11 families were enrolled. Sixteen patients were included in the analysis (2 patients had low com- pliance for treatment). The mean T SD age at last evaluation was 35.0 T 9.2 years (range, 16Y45 years). After their diagnosis, at age 22.6 T 10.8 years, all patients were treated with CDCA. Patients who started treatment after the age of 25 years had worse outcome and were significantly more limited in ambulation (P = 0.004) and more cognitively impaired (P = 0.047). Five patients who started treatment after 25 years of age contin- ued to deteriorate despite CDCA treatment. Conclusions: Beginning CDCA treatment as early as possible is crucial to preventing neurological damage and deterioration in CTX. After significant neurological pathology is established, the effect of treatment is limited and deterioration may continue. Key Words: cerebrotendinous xanthomatosis, Jewish-Moroccan, chenodeoxycholic acid, prognosis (Clin Neuropharm 2013;36: 78Y83) C erebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease caused by deficiency of the mitochondrial enzyme sterol 27-hydroxylase due to various pathogenic mutations in the CYP27A1 gene. 1,2 Sterol 27- hydroxylase has an important role in the metabolic pathway of cholesterol, catalyzing the oxidation of sterol intermediates, and its deficiency results in defective bile acid synthesis, with de- creases in chenodeoxycholic acid (CDCA), and elevated levels of cholestanol in plasma, urine, and various tissues. 3 Cerebrotendinous xanthomatosis is associated with con- siderable variability in disease onset, developmental manifes- tations, neurological deterioration, and systemic involvement, even among patients within the same family. 4 Neurological deterioration due to cerebellar, pyramidal, and extrapyramidal system involvement, as well as cognitive decline, psychiatric symptoms, epileptic seizures, and peripheral neuropathy usually become evident in the second or third decades of life. 5 Treatment with CDCA produces a reduction in cholestanol synthesis and plasma levels. 6 It has been suggested that CDCA prevents or arrests disease progression and in some cases, par- ticularly in children, reverses neurological deficits. 7Y10 Two clusters of CTX exist in Israel: one in families of Jewish North African origin with a predilection for Morocco 4,11 and another in families from Druze origin. 12 The purpose of this cross-sectional report is to assess the neurological outcome of 18 Jewish patients with CTX, with reference to the timing of treatment initiation and adherence to medication, in an attempt to reevaluate the role of CDCA treatment in CTX and to identify both negative and positive prognostic factors. MATERIALS AND METHODS Data were obtained for all patients with a diagnosis of CTX treated at our clinic during the years 2003Y2012. The study was approved by the ethics committee at the Chaim Sheba Medical Center (institutional review board registration number 8111-10- SMC). Patients’ conditions had been diagnosed based on clin- ical features alongside elevated plasma levels of cholestanol and, when possible, identification of disease-causing mutations in both alleles of the CYP27A1 gene. Clinical data were col- lected, and a complete neurological evaluation was performed at last follow-up. Neurological signs and symptoms were scored (usually from 0 to 3, where 0 = absent, 1 = mild, 2 = moderate, and 3 = severe involvement), including dysarthria and cognitive, cerebellar, pyramidal, and extrapyramidal system involvement. The Mini Mental Status Examination was performed, 13 and ambulation was scored according to the Hauser ambulation in- dex (HAI). 14 Statistical Analyses Scatter plots and Spearman rank correlation coefficients were calculated to test the relationship between age of CDCA treatment initiation and the various neurological deficits. End points of neurological status were cognitive deterioration, dys- arthria, pyramidal and cerebellar dysfunction, psychiatric dis- turbances, and HAI. A cutoff age of treatment initiation for detrimental outcome was determined based on scatterplots. A Mann-Whitney U test was performed to calculate differences in various parameters in the group of patients who started CDCA at an early age compared with those who started CDCA at a later age. All analyses were calculated also separately for men and women. Multivariate analyses were not implemented owing to small sample size. All analyses were performed with SAS sta- tistical software version 8.2 (SAS, Inc, Cary, NC). P G 0.05 was defined as statistically significant. ORIGINAL ARTICLE 78 www.clinicalneuropharm.com Clinical Neuropharmacology & Volume 36, Number 3, May/June 2013 *The Parkinson Disease and Movement Disorders Clinic, †Department of Neurology and Sagol Neuroscience Center, ‡Stroke Center, and §The Bert W. Strassburger Lipid Center, Chaim Sheba Medical Center, Tel-Hashomer, Israel; and ||Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare. Address correspondence and reprint requests to Sharon Hassin-Baer, MD, The Parkinson Disease and Movement Disorders Clinic, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel; E-mail: shassin@post.tau.ac.il Copyright * 2013 by Lippincott Williams & Wilkins DOI: 10.1097/WNF.0b013e318288076a Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.